OncoBriefs: Antibody Active in First- and Second-Line CRC

Highlights from the World Congress on Gastrointestinal Cancer

Action Points

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Patients who received cetuximab (Erbitux) in first-line therapy for metastatic colorectal cancer (CRC) continued to benefit from the monoclonal antibody as part of second-line therapy, a randomized trial showed.

The second-line combination of cetuximab and FOLFOX chemotherapy led to a median progression-free survival (PFS) of 6.4 months versus 4.5 months with FOLFOX alone. The difference did not achieve statistical significance in the intention-to-treat analysis but did result in statistically significant improvement in PFS in the subset of patients whose tumors did not have mutations in any of four key cancer genes -- KRAS, NRAS, BRAF, and PIK3CA, reported Fortunato Ciardiello, MD, PhD, at the World Congress on Gastrointestinal (GI) Cancer in Barcelona.

"In the patients with at least one mutation in one of these genes, there was a detrimental effect from FOLFOX plus cetuximab in progression-free survival, response rate, and overall survival," Ciardiello said in a statement.

Data analysis included 153 patients with metastatic CRC who had benefited from first-line treatment with cetuximab and FOLFIRI chemotherapy. At disease progression, the patients were randomized to receive FOLFOX alone or in combination with cetuximab. The primary endpoint was PFS.

Genomic analysis of tumor specimens from 117 patients showed that 66 had quadruple wild-type tumors, and the remaining patients had tumors with a KRAS or NRAS mutation. Patients with quadruple wild-type tumors had a median PFS of 6.9 months with cetuximab and FOLFOX versus 5.3 months with FOLFOX, representing a 44% reduction in the hazard for progression or death (HR 0.56, 95% CI 0.33-0.94, P=0.025).

In contrast, patients with mutated tumors had a median PFS of 2.7 months with cetuximab versus 4.4 months with FOLFOX alone.

"This is a new understanding of how to treat a select group of patients that are wild type for the KRAS, NRAS, BRAF, and PIK3CA genes who can be treated with the same anti-EGFR antibody and a change in chemotherapy following progression," said European Society for Medical Oncology (ESMO) spokesperson Andres Cervantes, MD, of the University of Valencia in Spain.

Controlling Chemo-Induced Side Effects

Patients with metastatic CRC had significantly less nausea and vomiting if they received an NK1 antagonist during treatment with moderately emetogenic chemotherapy, according to another conference report.

The addition of aprepitant (Emend) to a 5-HT3 antagonist and dexamethasone was associated with a significant increase in the rate of complete response in women and men treated with oxaliplatin-containing chemotherapy regimens as compared with a standard two-drug antiemetic regimen. The rate of complete response (no nausea or vomiting) in the 413-patient trial increased from 64% to 78% in women and from 81% to 90% in men, Junichi Nishimura, MD, of Osaka University in Japan, and colleagues reported.

The results have "opened the window to evaluate NK1 antagonists for emesis prevention in patients taking oxaliplatin chemotherapy," according to Fausto Roila, MD, of Santa Maria Hospital in Terna, Italy.

"Until now we said that NK1 antagonists have no role in the prevention of emesis in oxaliplatin chemotherapy, classified as having a moderate emetogenic risk only," said Roila, a spokesperson for the ESMO, which hosts the GI cancer congress.

Roila was referring to an earlier trial that showed no difference between the three- and two-drug antiemetic regimens among patients receiving moderately emetogenic chemotherapy. Because of the contrasting results, "we need to await new data from other studies before we can conclude whether or not NK1 antagonists can be added to a 5-HT3 antagonist plus dexamethasone in patients treated with oxaliplatin-based chemotherapy," he said in a statement.

The analysis of results by patient sex addresses a disparity in the occurrence of chemotherapy-induced nausea and vomiting, which occurs more often in women than men.

"The inhibition rate was especially clear in females," Nishimura said in a statement.

The findings were among several featured presentations at the GI cancers congress, including the following presentations.

Low BMI Tied to Worse Survival in CRC

Smaller patients had the shortest survival in a pooled analysis of studies involving patients with metastatic CRC treated with bevacizumab (Avastin).

Median overall survival increased from 21.1 months for patients with a body mass index (BMI) <25 kg/m2 to 23.5 months for BMI of 25-30 kg/m2 to 24.0 months for patients with BMI of 30-35 kg/m2 and 23.7 months for patients with BMI ≥35 kg/m2 (P<0.05 for trend). The findings conflict with established evidence that obesity increases the risk of developing CRC and disease recurrence after treatment.

"There is evidence that, at least in the U.S., obese patients may be at risk to receive lower doses of chemotherapy, so we hypothesized that obesity would be associated with worse survival in patients with CRC," Yousuf Zafar, MD, of Duke Cancer Institute, said in a statement.

"Our primary finding was that obesity was not associated with worse survival in metastatic CRC," he added. "Contrary to our hypothesis, patients who had the lowest BMI were at risk of having the shortest survival. This effect persisted after adjusting for study, age, ECOG performance status, gender, and hypertension."

The analysis, which involved more than 6,000 patients, showed no association between BMI and PFS, although patients with the lowest BMI had the shortest PFS (10.0 months versus 10.5 to 10.9 months for other BMI categories).

The results suggest that "cancer-related cachexia overwhelmed any potential biologic harm from obesity or any potential inadequate dosing that obese patients may experience," Zafar said. "These results suggest that cachexia is a fairly strong predictor of outcomes in these patients."

Cachexia may also be a marker of intolerance to treatment, possibly leading to lower dosing, he added.

PFS Benefit Confirmed in Pretreated Metastatic CRC

Patients with previously treated metastatic CRC had a modest but significant improvement in PFS if they received the oral multikinase inhibitor regorafenib (Stivarga).

Median PFS was 2.7 months among 2,800 patients enrolled in the phase IIIb trial, consistent with results of two prior phase III trial. The phase IIIb trial was initiated to demonstrate the safety of regorafenib and expand access to the drug prior to its regulatory approval. Although 80% of patients developed grade ≥3 adverse events, the results were similar to those observed in the phase III randomized trials, according to Eric Van Cutsem, MD, of University Hospitals in Leuven, Belgium.

"We report on safety and progression-free survival in a large cohort of patients that more closely resembles daily clinical practice than the pivotal registration trial," Van Cutsem said in a statement.

"The findings add to our knowledge of how to select patients and how to manage toxicities," he added. "We need to establish clear guidelines on the management of adverse events to make taking the drug more tolerable for patients."

The value of the trial is that it "translates phase III data into the clinical routine, since patients had similar characteristics and pretreatment to what we see in daily practice," ESMO spokesperson Dirk Arnold, MD, said in a statement.

"There were no surprising findings in terms of toxicity," said Arnold, of Klinik für Tumorbiologie in Freiburg, Germany. "All of the adverse events were quite class specific and also likely manageable."

The trial "shows that we have further treatment options for metastatic CRC patients pretreated with chemotherapy and that this comes at the cost of a specific, but manageable, toxicity profile."

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